Oral mucositis is a dose-limiting consequence of cancer therapy, often leading to pain, treatment alterations, and decreased quality of life. The mechanisms underlying the pathogenesis of oral mucositis remain incompletely elucidated; as a consequence, optimal treatment strategies have not been established. Most research has focused on the toxicity of cancer therapy, using growth factors to boost regeneration of quickly proliferating epithelial cells destroyed as a bystander effect of cytotoxic agents. Our interest in its pathogenesis lies in the inflammatory response mediated by pro-inflammatory cytokines, particularly TNF-alpha, which initiates mucosal signaling, the resultant inflammatory cascade, and the upregulation of proteolysis and apoptosis resulting in tissue injury and pain. Because TNF-alpha is a key early mediator of inflammation, it is an ideal therapeutic target for mucositis. Among the available TNF-alpha inhibitors, we select thalidomide. Our preliminary data suggest that thalidomide is bioavailable at the tissue level when topically applied and is present in the saliva of patients with mucositis. Available evidence suggests that administration of thalidomide topically will suppress the mucosal inflammatory cascade without the high circulating drug levels and adverse effects associated with enteral thalidomide. However, prior to further development of this intervention it is necessary to establish safety, tolerability, dose, and dosing interval in human subjects. We will test our hypotheses in three specific aims utilizing pharmacologic and molecular approaches in healthy volunteers and patients with oral mucositis. The first two Aims will test the hypothesis that topical thalidomide demonstrates tolerability and safety as measured by incidence of adverse events and plasma drug concentrations with increasing dose in healthy volunteers (Aim 1) and in patients with mucositis (Aim 2). Aim 3 will establish proof of principle by correlating the pro-inflammatory cytokine TNF-alpha with the clinical sign of mucositis and the symptom of pain, and will refine data collection techniques in the outpatient setting. Analysis of these data will contribute to dose selection, timing of intervention and observations, and molecular and clinical endpoints to be evaluated in a future Phase ll/lll study of topical thalidomide mouth rinse for mucositis. Demonstration of safety and tolerability will provide a basis to test further this route of administration. Hence, this proposal holds promise for clinical application in a relatively short period. [unreadable] [unreadable]